Melanoma is a cancer that begins in the melanocytes. Melanocytes, the cells that can become melanoma, are also found in the epidermis. These skin cells make a brown pigment called melanin, which gives the skin its tan or brown colour. Melanin protects the deeper layers of the skin from some of the harmful effects of the sun. For most people, when skin is exposed to the sun, melanocytes make more of the pigment, causing the skin to tan or darken. Melanoma accounts for less than 2% of skin cancer cases but causes a large majority of skin cancer deaths. Melanoma is a cancer that begins in the melanocytes.
Melanoma remains a highly morbid disease and its incidence has continued to rise sharply over the past few decades. Overall incidence rates for melanoma are increasing among men and women. Since 1981, the rate of increase has been about 3% per year. According to estimates from the American Cancer Society, there were about 59,580 new cases of melanoma in the U.S. in 2005, and about 7,700 people died of this disease. Prior to 2009 the only FDA approved treatments for metastatic melanoma included dacarbazine, interferon-alpha, and interleukin-2. However, the prognosis of patients with disseminated disease remained poor, with a 5-year survival rate of 16% or less in the U.S. New treatments such as anti-angiogenic agents, Raf, Mek and other kinase inhibitors and vaccines are currently being developed and may offer improvements in survival for patients with this disease. In addition, the toll of melanoma in terms of “life-years lost” is the highest of all solid tumours in the United States.
For the diagnosis of melanoma a surface skin biopsy, punch biopsy or excisional biopsy is taken. Based on a primary biopsy diagnosis nearby lymph nodes may be biopsied to see if the cancer has spread. Staging of melanoma is based on the American Joint Committee on Cancer (AJCC) TNM system. The T stands for tumour (how far it has grown within the skin and other factors). The T category is assigned a number (from 0 to 4) based on the tumour's thickness (how far down it has grown). N stands for spread to nearby lymph nodes (bean-sized collections of immune system cells, to which cancers often spread first). The N category is assigned a number (from 0 to 3) based on whether the melanoma cells have spread to lymph nodes or are found in the lymphatic channels connecting the lymph nodes. The M category is based on whether the melanoma has metastasized (spread) to distant organs, which organs it has reached. According to these standards the different stages and survival in the US are as follows:                Stage IA: The 5-year survival rate is around 97%. The 10-year survival is around 95%.        Stage IB: The 5-year survival rate is around 92%. The 10-year survival is around 86%.        Stage IIA: The 5-year survival rate is around 81%. The 10-year survival is around 67%.        Stage IIB: The 5-year survival rate is around 70%. The 10-year survival is around 57%.        Stage IIC: The 5-year survival rate is around 53%. The 10-year survival is around 40%.        Stage IIIA: The 5-year survival rate is around 78%. The 10-year survival is around 68%.        Stage IIIB: The 5-year survival rate is around 59%. The 10-year survival is around 43%.        Stage IIIC: The 5-year survival rate is around 40%. The 10-year survival is around 24%.        Stage IV: The 5-year survival rate is about 15%-20%. The 10-year survival is about 10%-15%.        
Melanoma treatment options are based on the stage of the disease and may include: surgery, chemotherapy, targeted therapy, immunotherapy and radiation therapy. Early-stage melanomas can often be treated effectively with surgery alone, but more advanced cancers often require other treatments.
Activating B-RAF V600E kinase mutations occur in 7% of human malignancies and 60% of melanomas. These changes cause the gene to make an altered BRAF protein that signals the melanoma cells to grow and divide quickly. A number of kinase inhibitors addressing BRAF and other kinase targets in the pathway including MEK have been approved for clinical use. These compounds include Vemurafenib (PLX4032 or RO5185426), Dabrafenib (GSK2118436) and Trametinib (GSK1120212). Several other kinase inhibitors are currently in clinical development for melanoma including AB1010 (Masitinib), AEB071 (Sotrastaurin), AG013736 (Axitinib), AMN107 (nilotinib), ARQ 197 (Tivantinib), ARRY-438162 (Binimetinib), AS703026 MSC1936369B (Pimasertib), AZD2644 (Selumetinib), BAY 43-9006 (Sorafenib), BEZ235 (Dactolisib), BKM120 (Buparlisib), BMS-908662, CEP-32496, E7050 (Golvatinib), E7080 (Lenvatinib), GDC-0973 (Cometinib), LEE011 (Ribociclib), LGX818 (Encorafenib), LY2801653, LY3009120, MLN2480, P276-00 (Riviciclib), PD-0325901, PLX3397, PLX3603, Vemurafenib, PLX7486, PLX8394, PX-866 (Sonolisib), RAF265, RO4987655, SAR260301, TAK-733, TK1258 (Dovitinib), XL184 (Cabozantinib) and XL281.
While early-stage melanomas can often be cured with surgery, more advanced melanomas can be much harder to treat because standard cancer treatments such as chemotherapy are not very effective. But in recent years, newer types of immunotherapy and targeted therapies have changed the treatment of this disease, and many new treatments have shown a great deal of promise in treating advanced melanomas.
In particular, stage IV melanomas are very hard to cure, as they have already spread to distant lymph nodes or other areas of the body. While the skin tumours can often be removed by surgery or treated with radiation therapy, metastases in internal organs which cannot be removed may be treated with radiation, immunotherapy, targeted therapy, or chemotherapy. In about half of all melanomas with mutations in the BRAF gene, treatment with targeted drugs such as vemurafenib, dabrafenib and trametinib are used. These drugs can help some people live longer, although they have not been shown to cure these melanomas. Even though the outlook for patients with stage IV melanoma tends to be poor overall, a small number of patients respond very well to treatment and survive for many years after diagnosis.
Unfortunately, also most anti-tumour treatments are associated with undesirable side effects, such as profound nausea, vomiting, or severe fatigue. Also, while anti-tumour treatments have been successful, they do not produce significant clinical responses in all patients who receive them resulting in undesirable side effects, delays, and costs associated with ineffective treatment. Therefore, biomarkers that can be used to predict the response of a subject to an antitumor agent prior to administration thereof are greatly needed.
Given the high incidence of melanoma and limited efficacy of current treatments, a melanoma biomarker and assay for a melanoma biomarker is needed that could serve as an accurate early indicator for therapeutic response in a mammalian subject to measure the effectiveness of candidate melanoma inhibitory agents.
In view of the above, there remains a pressing need for methods that provide a fast and accurate prediction of the response of a patient diagnosed with melanoma to targeted pharmacotherapy. These methods would enable to provide information regarding the efficacy of the targeted pharmacotherapy treatment, and more specifically provide an early determination of the most suited treatment of the melanoma patient.
The present invention aims at providing methods and devices for predicting the response of a patient diagnosed with melanoma to targeted pharmacotherapy. The present invention also aims to provide methods and devices for predicting the response of patients diagnosed with melanoma to specific medicaments. The method of the present invention therefore adds to the existing assays currently used to select therapies in melanoma patients.